CA2190155A1 - Oxaboroles and salts thereof, and their use as biocides - Google Patents

Abstract

The use of oxaboroles and salts thereof as industrial biocides especially fungicides for the protection of plastics materials such as plasticised PVC. Preferred compounds are 5- and 6-fluoro or bromo- 1,3-dihydro-1-hydroxy-2,1-benzoxaborole including O-esters thereof.

Description

WO 9sl337s~ PCT/GB95~0120(i ~ 2T~0155 OXAEOROLES AND SALTS THEREOF, AND THEIR USE AS BIOCIDES
The present inventlon relates to the use of nv~hnrnlpq and salts thereo_ as ;n~llcfr;~l biocides, especially flmriritlPq, biocidal t;rnq rrnt~;n;nr the oxaboroles including their salts and certain nY ~hnrnl PR, S No sirgle ;n~llqtr;~l h;nr;rl~ is ideal for all :lr,nl;r~~;nnq and new biocides are constantly being sought with better activity againqt individual spoilage micro-org=anis~ns, wid=er spectrum of activity, improved rr~r~t;h;l;tr with the medium in which they are used and im,pro~ed rL~rc;qtPnrp in use. Safety in use is another important rn~qi~~1Pr~t;rn A small number of comDounds rnnti:in;nri ll L~ULUle ring (.rereinafter "oxaborole") have already been described in the litPr~tllrP
These are N- (l, 3-dihydro-1-hydroxy-2, 1-~ ,l -6-yl) -cllrr; r acld (C~ 5~ 23423c); 4-(1,3-dihydro-1-hydroxy-2,1-l~ 1 -6-ylazo)-2-naphthoic ~cid (CA ~ 23423c); 1,3-dihydro-l-hydroxr-6-nitro-2,1-l, ,,,,.~l~,,~le (CA ~;~ 23423b); 6-amino-1,3-dihydro-1-hydr~r-2,1-and its hy~irrrhlnrirlp ~C'A 23423c); 1,3-dihydro-1-hydroxr-7-methyl-2,1-hPn7rY~hnrole ~CA ~ 6473f) i 1- (benzyloxr) -1, 3-dihydro-2,1-l r~ .lP (CA 61 16084f); 1,3-dihydro-1-hydroxy-N,N-dimethyl-2,1-l , ~ , .,1 -6-amine (CA 1~1(3) 22633f); 4-bromo-1, 3-d_rlydro-1-hydroxy-2,1-hPn7nY~hnrole (CA 10~(3) 22633f~; l,1'-oxybis[4-bro~o-1,3-dihydro-2,1-h~n7nYAhnrnl~ (CA 1~1(3) 22633f); 1-(cyclohexyloxy)-1,3-dihydro-2,1-l,~ ,le ~(CA 61 16084f); 1-ethoxy-1, ~ -dihydro- 2 ,1 -l ~ l K, . ( ,l P ( CA 61 160 a4f ) i 3 r 7 -dihydro - 1, 5 - dinvdroxr-~:L-,3P-benzo[1,2-c: 4,5-c'~bis[1,2~oYaborole (CA 61 14698a); 1,3-dihydro-l- lvdroxr-6-methyl-2, 1-l~ TP (CA 61 14698b); 5-bromo-1, 3-d~ydro-l-hydroxr-2,1-hPn7rYz~hrrnlo-6-methanol (CA 51 14g98b); 1,1'-oxyDis[1,3-dihydro-2~1-T~Pn7ny~hnrole~ ~CA 103~3) 22633f); and bornnnrhth~ P (CA 116(13) 129587q). French certificate of utility No 73 29370 discloses T"""""~ P (l-hydroxr-3H-1,2-l,~ ,le) and ~is is the only citation known which discloses that an oxaborole is h rlr~ir~lly active. It is disclosed as being useful in ;nhihitinr the growth of micro organisms in a~iation fuels. ~owever, at :least lOOppm o- -~he hnrnnnrhth~liriP is required to protect the fuel.
It has now been found that compounds rrnt~;ninr an o~horole r--.g are particularly effective against micro-organisms such as bac~eria, algae, yeasts and particularly fungi, especlally fungi which cause rlPrir~tirn of plastics materials. The level of micrnhinlnrir~l ac~ivity now found is sllrrriqing in the lighnt of the disclosure in the aDove utility certificate.

WO gS/337~ 21 ~ O 1 55 PCT/GB9S/01206 According to the present invention there is pro~ided a method ior tle ~rnt~-tinn of a medium s"s~-~t;hll~ to microbial attacc by tbe treatment of the medium with an effective amount of an Qxaborole of ~
general formula (1) S
\~A ~
~1 / _ or a salt thereof wherein A and D are each i.ld~ ly, hydrogen, Q7~tiQnally 5~h=tit~tf.~7 C l8-alcyl, aral.7cyl, aryl, or heterQcyclyl or where A and D
together with the carbQn atQms to which~they are attached fQrm a 5,~ or ~-membered iused ring which ltself may l~e suhstituted; ~ ~ ~
X is a grQup -CRlR2 wherei~ Rl and R2 are each, ;~,(7~ l ly, hydrQgen, optiQnally c"hsti tllt~f7 Cl 6-al7cyl, nitrile, nitro, aryl or =~
aralkyl or Rl and R2 together with the carbQ~l at to which they are~
attached form an alicyclic ring;
R is hydrogen, optiQnally sl~hst;t~t,~7 Cl lh-alkyll aral.7cy:L, aryl, heteroaryl, cycloal7c~1 or a radical Qf formula (2~ ~=
\~b ~
.~
25 . wherein A, D and X are as hereinbefore defined except where: the medium is aviatiQn fuel and the Qnly Qxahorole is IK~ 7f~
When A and/or D is alkyl, IF may be linear or branched and is preferably Cl l2-, more preferahly Cl ,- and especially Cl j-alFcyl ~~
When A and/or D is s~lhstit~t~7 alkyl, the s~hstit~ nt may be Cl 6-alkQxy, hydroxy, halogen, nitrile, amirro, s~hst;t~t~ amino~ ch~rbQxy, acyl, arylQxy or carbQnylamino QPtiQnally s--hstit~t~7 by Cl -alkyl.
When A and/or D is alkyl the alkyl group or 2roups are ~=
preferably lmsllh5titllt,~7 ~en A and/Qr D is aryl, it is pr~ferably phenyl which may 3'i itself be substituted ~ :
h7hen A and/or D is aralkyl, it is preferably benzyl or 2-ethylphenyl, where the phenyl ring may be 5,.hstit"t..,7 When the phenyl ring is s~hst;t~t~7, the s~hstitl~nt.s include Cl ~-alkyl, Cl 6-alkoxy, arylQxy, hydrQxy, halogen~, nitro', ,7n2 5~1 ` ~7n, tri~l hyl or amino QptiQnally .sl~hstit~t~7 by Qne or more Cl 6-alkyl grQups ArylQxy is ?referably phenQxy :

When A and D together with th~ two carbon atoms to whlch they are attached form a fused ring the ring may be alicyclic as in cyclopentene, cyr1nh-x-~P or cycloheptene or it may be aromatic such as phenyl, pyridyl, thienyl or furanyl. The fused ring may also carry substituents as described hereinbefore for substituted phenyl and substituted alkyl. The fused ring may also cnntAin more than one ring system, for example, a naphthyl or ~l;nnl;nyl ring system or the fused ring may also link two oY~borole rings as for example in lH,3H-benzo[1,2-c: 4,5-c']bis[1,2]oxaborole.
When R1and/or R2 is aryl it is preferably phenyl.
When Rl and/or R2 is aralkyl it is preferably benzyl.
Preferably, at least one of Rl and R2 is h~d~uy~Ll and it is especially preferred that both are h~dLu~
When R is alkyl it may be linear or branched and is preferably C1l2- and PspPciAlly C16-alkyl.
When R is substituted alkyl, the substitutent may be Cl6-alkoxy, Cl6-alkylthio ~hydroxy, amino, substituted amino, carboxy, aryl, aryloYy, cArhnnAmid optinnAlly substituted by Cl6-alkyl, aryl such as phenyl and aralkyl such as benzyl.
When R is aralkyl it is preferably benzyl or 2-ethylphenyl.
When R is aryl it is preferably phenyl.
When R is heteroaryl it is preferably ~;nol;nyl and particularly ~l;nnl;n-8-yl.
When R is cycloalkyl it is preferably cyclohexyl.
When the substituent is hAlo~n~ it is preferably bromine, chlorine and PspeciAlly fluorLne.
Cne preferred class of oxaborole is a hPn~y~horole of formula 1 wherein A and D to~eth~r with the carbon atoms to which they are attached form a fused phenyl, naphthyl or thienyl ring.
When the fused ring is phenyl, the oxaborole is a h~,~7~,x~horole and the substituent or substituents may be in any of positions 4,5,6 or 7 of the h~ x~horole. Preferably the substituent or substituents is/are in the 5 and/or 6 position. Preferred substituents are amino, alkyl, alkoxy, phenyl, ph~u~, sl~lph~nAm;de, rArh~nAm;~, each of which may be substituted, and also trifluor~",ethyl, chlorine, bromine and ~Sper;Ally fluorine.
When the fused ring is naphthyl, the other fused phenyl ring is attached to the benzoxaborole ring system in either the 4,5- or 5,6-position.
In one preferred class of oxaborole, R is h~dluy~l.
Another preferred class of oxaboroles for use in the present invention is where R is substituted alkyl, Pcper;Ally where the substituent is a primary, secondary or tertiary amino group and WO 95/3375.1 2 ¦ 9 0 1 5 5 PCTIGB95101206 r~rr;r~ rly wherein the alkylene amino grou~ forms a~5-, 6- or 7- =:
melrhered rir,g together with the horon atom and the oxygen atom to which the group R is attach ed . Such compounds are esters ~ a -tPtrAhPAr;31 boron atom as for example in formula ~3) below~ ~

A X` ~ .
3~B~ N~R3R4 (3) wherein A,D and X are as defined h~rei3~h~33'-ore;
R3 and R~ are eac_ i ~ "1 "1 ly, hydrogen, optionally lS suhstituted Cl 1b-alkyl or cptionally S~qt;t11tPA phenyl or R3 together with Y or part of Y forms a 5- or 6- or 7-~ memhered optionally qllhstitlltPrl ring rnnti~;n;n~ the nitrogen atom; and ~ =
Y i8 an optionally sllhqt;tlltPA diTralent alkylene linking gro~ap nnntAin;n~ up to 18 carb~n atoms.
R3 and R4 are pre3Çerahly optionally substituted Cl l2-alkyl, more preferably optionally suhstituted C1 b-alkyl and especially s-hCt;t..tPA Cl 6-alkyl, It is pre3 erred that when R3 and~or R~ is alkyl the aLlcyl group is unsuhstituted.
Ihe alkyIene gmup rPrrPqPntPA hy Y may he linear or =
bran~ed.
When Y is q11hqtit1.tPA alkylene the q11hctit11~nt is preferably phenyl, C1 6-alkoxy, C1.6-alkylthio or carbonyl~aIkylene as for exampIe a -COCH2- group.
Wnen Y or part of Y forms a 5-, 6- or 7- membered optio3lally s11hqt;t-1tPA ring the ~q11hqt;t1lGnt may be a fused ring which may itself be ql -hq t i tl l t PA
Preferably Y is 11nq11hqt;t11tPA alkylene.
When R3 together with Y forms a 6-membered optio3~ally qlhqtitlltPA ring the ring~is~preferably a ouinolinyl ring as nhtAinAhlP,:
for example, from 8-hydroxy~I~l;nnl;nP =~
When R3 together with part of Y forms a 5 ,.~ Lr~l ring the riny is preferably ryrrolidin-2-yl.
It is preferred that A and D together with the carbon atoms ~0 to which they are attached form an aromatic ring or ring system such as fo- example a fused ~enyl, ~thienyl or~3laphthyl ri3lg which ring or ring sys~em may be qllhqt;tlltPA as defined hPrP;nhPl~nre for substituted phenyl and .q11hst;t11tPA alkyl.

WO 95/3375.1 , ~' 2 1 9 0 1 5 5 PCT/GB95/01206 s When A and 1: together with the carbon atoms to which they are attached form a fused phenyl ring which is c-lhqt;t-lto-l, th~e oxaborole may be a lX, 3~-benzo [1,2-c:4,5-c'] bis [1,2] oxaborole rnnt;~in nr an ester group attached to each borDn atcm.
S Ar~rt;rlll~rly preferred class oi MQ orole of formula 3 i6 that of formula 4 A X
~0 D ~ B--I HR3 O\
(R6 ~Tn . ~ ~ =
wherein A, D and X are as defined horoinhofnro;
n is 1, 2 or 3;
R3 is hydrogen, optionally s -hqtit1lt~ CL l6-alkyl or optionally :sllhstitlltP-l phenyli Rs and R6 are each ;"(l~ ly, hydrogen, optionally r~lhqt;tlltoll. alkyl rnnt~;n;ng up to a total of 16 carbon atoms or optionally ylhst;tllto~l phenyl.
Preferably Rs and R6 are each, ;"~ ly, optionally rllhqt;tllto~ Cl 6- and especially optionally qllhst;tll~ Cl ~-alkyl.
Preferably two Df R3, R5 and R6 are hydrogen It is especially preferred t~at R5 and R6 are bot~ hydrogen.
Pre~erably n is 1 or 2 and especially 1.
When A and/or D and/or R is a group which is or co~tains halDgen the halogen may be ~luorine, chlorine, bromine or iodine. When A and/or D is alkyl qllhst;t~lto~ by halogen, it may cDntain mDre than one halogen atom as in tr; fl hyl .
When A and D together with the two carbvn atoms to which they are attached _orm a fused ring, any 5 lhstitllont in the fused ring is preferably attached to a carbon ato~ othOE thi~n that adjacent to the oxaborole ring~ -Thus in the case of 1,2-dihydro-2,1-~ "vles the 5llh5titll0nt or qllh5t;tll0nt5 are preferably in the 5 and~or 6 position.
When the ox~vrole o_ _ormula l is a salt, the group -OR attached to the boron atom is ionic as in _O`Rt where R~ is an alkali metal such as lithium, potassiUm or sodiu~ or R~ is an amine salt or ~uaternary ammonium cation. In the latter case the r~uaternary ammDnium ion may itself be m;rrrh;rlr~ir~lly active.
_ ~

WO 95/337~ 21 9 0 1 5 ~ PCTIGBg5/01206 ?*?hen A and/or D is amino or sllhct;tlltp~ amino, or whe?l A
and/or D and/or R contairs amino or s~hct;t--tP~? amino the salt of t_e oxaborole of for~ila I may be the salt of an or~?aniC or inorganic acid.
~xamples of such acids are acetic and hydrochloric acids.
Particularly useful effects have ?~een obtained tn plastics materials and pairt filn?s where the cnmpound rnntA;n;nr~ an ox3borole ring is l,~ le or the ~;-chloro-, 5-chloro-,= 5-fluoro- or S-bromo-der_vative t~ereof and the oxaborole esters nhtA;nAhlP thereErom by reactiOn with Al? nPq 6uch as PthAnnl nP, 3-aminn?propanol and ~1 . nnh?ltAnnl, The oxaborole may be used in undiluted form but is preferably fn?m?llAtP-l in a, , t;nn to~ether with a carrier. Thus, as a further a6pect of the imrention there is ?~?roVided a, , t;nn ~ q;nrJ a carrier arld an oxaborole of general formula (1) or a salt thereof (hereinafter ~biocide, t;nn~ with the proviso that when bUL~ lP is the nnly oxaborole present the carrier is not a aviation fuel.
The carrier may be a material which shows little, if any, antimicrobial activity and may be, or include, a medium whi& is susceptikle to the growth of micro-orgarisms, such as bacteria or f?lngi.
The carrier may be a solid but is preferably a liquid medium and the biocide ~ , t;nn is preferakly a so~ution, s~qrPnq;nn or emulsion of the r~xakorole in a lio,uid medium.
The carrier is generally selected so that the biocide =
rr~?nq;tinn is-~ , ;hlP with the medium to be rrntPrtP~ ~ Thus, for example, if the medi?~?m to ke rrntPrtPr? is a solvert-kased paint, lacquer or varnish the carrier is preferably a solvent, especially a non-polar solvent such as white spirits.
If the medium to~be protected is a plastics material, the carrier is ?~eferably a rlAqtlr;qPr or qtAh;l;qPr typically used in~ he ~Ahr;rAt;nn of plastics articles such as dioctylr?~thAlAtPl dioctyladipate or~prn~;~;qp~l soya bean oil. If the medium to be pro? ected is an ao,ueous medium, the carrier is preferakly water or a water-miscikle organic solvent or ?ni~cture thereof ?3xamples of suitakle water-miscible organic solvents are acetic acid, N,N-~imethyl' '~1P, dimethylqlllrhn ;flP, N-methyl-2-pyrrolidine, alcohols such as ethanol or glycols such as ethyle?1e glycol, propylene glycol ard dipropylene gl~ycol and lower C, ~-a~?,~yl carbitols such as methyl carbitol. If the carrler is a solid, the t;on may be a dry solid as descriked in EP 407024.
If the biocide tinn is in the form of a qllqrPnqinn or emulsion, it preferably also contains a surface active agent~to produce a stable ~?;;qrPrqion or to maintain the non-rnnt;mm~q phase uniformly fl;qtr;hlltPr thrn?~rJhnlt the rnnt;nln?lq phase. Any surface active agent .~ , which does not adversely affect the biocidal activity of the compound of formula I may be used, for example alkylene oxide adducts of fatty alcohols, alkyl ph~nc~1~, amines such as ethylene ~ m;n~ and anionic surfi~tAnt~ such as adducts of ni~hthc~l s1~1ph~ni~tes and formaldehyde.
The c~ t~dtion of the oxaborole in the biocide composition is preferably up to a level at which the biocide composition is stable under the conditions of storage or tL~ ~c~LLation and is preferably frcm 1 to 50%, ~spe~ lly from 5 to 30% and more ~pe~ lly from l0 to 20% by weight relative to the total weight of the biocide cc7mrosition.
As noted hereinbefore, many of the oxaboroles are new.
According to a further aspect of the in -ntion there is provided a c~rolln~ of formula (l) :~,\, , `:
or a salt thereof wherein A, D , X and R are all as hereinbefore cl~f;n~ except for N~ 3-dihydro-l-hydroxy-2~l-h~ x~hnrol-6-yl)-sll~c;nAm;c acid; 6-nitro-, 6-amino-, 7-methyl-, 6-(NN-dimethylamino)-, 5-(NN-dimethylamino)-, 4-bromo-, 6-methyl-, 5-bromo-6-methylol-l,3-dihydro-l-hydroxy-2,l-h ,l~ hnrolei bOL' ~ L ~h IhAlic~P; l-benzyloxy-, l-cyclohexyloxy-, l-ethoxy-l,3-dihydro-2, ~ 117~ role;
l,l'-oxybis[1~3-dihydro-2~l-h~ x~hnrole]; 1,1'-oxy~is [4 -bromo-l,3-dihydro-2,l-h~n7nx~horole] and 3,7-dihydro-l,5-dihydroxy-lH,3H-benzo[l,2-c: 4, 5-c']bis[l,2]oxaborole.
Preferably A and D to~eth~r with the carbon atoms to which they are attached form a fused phenyl ring which may itself be substituted as ~f;n~cl hereinbefore and preferably R is h~dl~y~ or alkyl substituted by amino. It is also preferred that X is -CH2-.
Preferably the fused phenyl ring cnnti~;n~ a halogen atom in the 5 and/or 6 position of a h~7~ horole ring system, especially in the 5-position. Preferred halogens are fluorine and chlorine. Examples include 5-chloro and ~Cpe~jAlly 5-fluoro h~ll7l~x~horole.
Other preferred oxaboroles are the O-esters obtA;nAhle by reActing the oxaborole with an AminC~ hAtic carboxylic acid such as glycine or an alkAnnlAm;n~ such as ethAnnli n~, 3-Am;.l~,~,Lc~ ol or 4-i~m; nnhl~ti~nnl .

WO 9~/3375~ ~ PCT/GB~'i/01206 219~

Acrording to a further aspect of the iIlvention tbere iq provided a com~ound of formula 3 ~ ~ (3) o~
wherein A,D and X are as defined hereinbefore; - -R3 and R~ are each, ; " 1~ ly, hydrogen, optionally substituted C, l3-alkyl or optionally q~hctit~t,~rl phenyl or ~3 toge~her wi~h Y or part of Y forms a 5-, 6- or 7-membered ring rrntAin;nr~ the nitrcgen atcm; and Y is an optionally substituted divalert alkylene linking group rrntAin;n~r up to 18 carbon atoms _ _ The rY ~hrrnl f~q may be made by ~ny method known to the art.
Thus, the 1,3-dihydro-1-hydroxy-2,1-l~ ""lPc may be made by reacting an ortho-toluidine under Sandmeyer rrn~lt;rnq to obtain an O_ ~hctit~tf.~l halo,eno to+uene which is then reacted with magnesium or al3cyl lithium such as butyl lithium in an inert solvent ar~ the Grionard reagent or aryl lithium so formed is reacted with a horste sster such as trihutyl borate to obtain a toluene boronic acld. ~ This horonic acid is then reacted with a hrominating agent such as N-l~ ",, in~m;~l~ in an inert solvent such as Æbarl tf~trArhlrr;~f~ to giYe a hromcmethylhenzene boronic acid which is hydrolysed in alkali to give the hydroxymethyl analo3ue which i5 finally cyclised to give the b~n7rY~hnrrlf~ un~ier acid rrn~;t;r,nc This is method A. Tbe rrerArAtion of o-bromomethyll,~ ;r acids is described in JACS 1958 80 835.
Alternatively, an appropriate benzaldehyde is reacted with p-trl~nf.c~lrhrnylhydrazide in an inert solvent such as dry dichluL~,..~tl~lt: and the product ~s ~ ly reacted with horon trihrrmi~- ir the presence of a catalyst such as ferric or-aluminium chloride and tben cyclised to give a 1,2-dihydro-1-hydroxy-2- (4-methylphenyl-sulphonyl) -2r3l l-h~n7mliA7Ahrr;nl~ This is ~ l ly hydrolysed under alkaline rrn~;t;rnq and then c~verted to the bPn7rYAhnrole under acid rrnr;t;rnc It is generally not necessary~to isolate the int/~rm~l;At~ rl;A7Ahnr;n~ This is method B and is descrioed in Iiehigs Ann. Chem 1935 683 --OYAhrrnl~c rrntA;n;n~ a fused aromatic ring can he made by reacting an aromatic compound rrntA;n;rrJ a -CE~ I group with alkyl or aryl lithium and an ~L,J,.,,,lY,,,,I,~ in a dry inert or,r~anic liouid.
-W 095/337~4 2 1 ~ O 1 5 5 PCTtGB95/01206 ~ , Accorr7;ng to a still further aspect of the invention there is provided a process for making an oxaborole cnnt;7;n;ng a fused aromatic ring which cnmrr;R~R rpArt;ng an aromatic csmro7m~7~ cnnt~n;ng a -CH20H
group with alkyl or aryl-lithium and an organo-borate in a dry inert organic liquid.
Preferably the fused arcmatic ring is a fused phenyl ring and the arcmatic crmpol-nn cnnt;7;ning a -CH20H group is an opt7nn;711y substituted benzyl alcohol.
Preferably the aromatic ccr~Jol7n~7 cnntA;n;ng a -CH20H group also cnnt;7;nR one or more further substitutents which are ortho-lithiation activating groups since these allow for reaction under milder conditions. Such activating groups are preferably located in a position(s) other than ortho to the -CH20H group. Examples of activating groups are C16-alkoxy, halogen such as chlorine and fluorine, substituted alkyl such as -CH20CH3, -CH2NT2, -CH2CH~NT2, substituted amino such as -NT2, -NHC`OT, -NHCO2T and amides such as -SO2.~HT, -SC~NT2, -CONHT and -CO.~T2 where T is aryl or alkyl. Preferably when T is aryl it is phenyl, and it is preferred that when T is alkyl it is Cl6-alkyl.
An alkyl lith;um ccmpcund is preferred which may be linear or branched and is preferably Cl6-alkyl and Psperi;711y Cl4-alkyl such as butyl lithium.
The organic liquid is preferably an alkyl ether such as diethylether or preferably a cyclic-ether such as tetrahydrofuran.
m e rP~rtinn may be carried out at t~ res up to the boiling point of the organic liquid. ~ , when the aromatic compound cnntA;n;ng a -CH20H group also cnntA;nc an ortho-lithiation activating group the rPActinn is preferably carried out below 0C and more preferably below -50C. It is ~pec;A11y preferred that the reaction is carried out beL~ -70 and -100C.
m e aromatic cn~Y m~ cnntA;n;ng a -CH20H group may also carry further substitnt~ntq which do not react with the alkyl or aryl lithium cr~r~m~.
m e organo-borate is preferably an alkyl borate which may be linear or hrAnrhP~ more preferably a C16-alkyl and especially a C14-alkyl borate.
sec-Butyl lithium and n-butyl borate are preferred.
me rPActjnn bet-l_cn the aromatic cn~r~m~ rnntA;n;ng a -CH,OH group and alkyl or aryl lithium is preferably carried out in the presence of a rhP1At;~ agent. me preferred rhPl~t;ng agent is tetramethyleneethylPnedjA~ine.
Oxaboroles cnntAining a fused aromatic ring can also be made by reacting an aromatic co~r~m~ cnntA;ning a -CH20H group and an ortho iodo or bromo group with alkyl or aryl lithium and an organo-borate.

WO 95l3375~ PCTIGB95lO 06 2t ~Ot 55 12 10 . = ~ .
Acoording to a still:furt~er aspect of-the invention t~ere is provided a process for making an oxahorole rrntA;nin9 a fused aromatic ring, c;nJ reactinrj an arr~-tir I ~ rrntA;n;ni a~ 2C~I group and an ortho iodo or bromo group wit~ alkyl or aryl lithium and an organo-borate in an inert organic liquid ~ :~
Preferred reaction rrnrl;tirnc æe a5 defined fQr t~e aromatic ccmpcund rrntA;ninr a 'CE~2C~I: group.
The boron esters of the c~aoorole are typically made by reaction of an cxaborole of formula 1 where R is~hyarogen with an appropriate amino-aliphatic carboxylic:acid or preferably an AlkAnrl n~ in an inert solvent at 25=125C when the boron ester is formed almost instAntAnPr~lqly. Preferably the inert solver~t forms :an a7eotrope with water to fAr;l;tAt~ remcval of water f~rmed when thë
AlkAnrl n~ is reactea Wl~i the cx~orole. It is especially preferred that the solvent is toluene This is method C
The oxaborole or cr~mpositions rrntAin;nr the oxaborole can be -used for the treatment of various meaia to inhibit the grr,wth of micro-organisms and are especially effective in providing snti f~ngal ~~~
activity.
As a further aspect of the~present invention there is provided a method for inh;h;t;nr the growth of micro-Prganisms on, or in, a medium which comprises treating the medium with an o~aborole or a biocide ~ 't;nn rrntA;n;nri an n~hn~nlP
The cxaborole can be used in rnn~;tirnq in which micro- ~
organisms grow and cause problems.~ Systems in which micro-organism-s cause problems include liquid, particuIarly ar1uecus, systems such as cooling water lir1uors, paper mill ~ir~uors, metal working fluids, .nlni;rAl drilling lllhr;rAntq, polymer emulsions and especially surface coating t;rnq such as paints, varnishes and lacquers and more especially solid materials such as wood, plastics materials and leather.
The r~hrrrlrq have been found particularly effective in inh;h;t;nr microbial ~rrAll~t;rn of plastics materials such as rlAqt;r;cP~ P~C and ure~hanes since they are not q;~nif;rAntly adversely affected by the high t~ ccmmonly used in the fAhrirAt;rn of such articles L~l thls respect the hPn7r~7rl~q have been found especially effective, oarticùlarly those rrntA~n;nri one or ~nore halogen qlhqtit~lPntq in the fused phenyl ring of the hpn7r~Ahnrole~ ~
The r.r~3hrrrlP can be included in such materials to provide an anti-microbial effect The amount of the compour~d is typically in the range from 0.00001 to 2.0% preferably from 0.0001 to 1~6 and especially from 0.0002 to 0.5%.by weight of the compound relative to the system to which it is added. In certain cases, microbial ;nh;hltinn has been obtained with from 0.0005% to 0.01~6 by weight of the oxaborole. Thus, wo ssn37s~ q O 1 5 5 PCT/GB95/0120~i '- '11 in the case of plastics materials the r~hnrr7F~q have bee~ found to inhibit microbial~,rowth at an applied ~ ;rn of less than Q.05%, particularly less than 0.01% and especially less than 0. 0059~i and more especially Iess th=an 0 . 001% .
Tbe 4xaborole may be the only ~ntim;rrrhii~l compound used to protect the medium or it may be used together with one or more different r.~hrrrl~c rr w;th rn.~ or more other comPounds having ~ntim;rrnhi~l activity. }~ mixture of anti-microbial compoun~c hereinafter referred to as a "biocide mixture" often bas a broader~anti-microbial spectrum and hence is more generally effective th n tbe ~ q of the mix~ure The other antimicrobial comPound or compounds may possess anti-bacterial, anti-fungal, anti-algal or other ~nt;m;rrnhi~l activity. The biocide mixture`typically contains from 1 to 99% by weight, and preferably from 40 to 60% by weight, o~ an oxaborole relative to the total weight o~~an-~~nt;m;rrrh;~lly active compound, in the biocide mixture. ~ ~ -Examples of other ~ntim;rrnh;~l comPounds which may be used, together with the oxaborole are ~uaterna~y ammonium comPoun~s such as N,N-diethyl-N-dodecyl-N-benzylammonium chloride;
N,N-dimethyl-N-octadecyl-N-(dimethylbenzyl)ammonium chloride;
N,N-dimethyl-N,N-didecylammonium chloride N,N-dimethyl-N,N-didodecylammonium chloridei N,N,N-trime~hyl-N-tetradecylammonium chloride;
N-benzyl -N, N- dimethyl -N ( Cl2 - Cl8 -alkyl ) ammonium chloride i N- (dichlorobenzyl) -N,N-dimethyl-N-dodecylammonium chloride;
N-hexadecylpyridinium chloride; N-hexadecylpyridinium bromide;
N-hexadecyl-N,N,N-trimethylammonium bromide; N-dodecylpyridinium chloride; N-dodecylpyridinium hiqlllrh~t,-; N-benzyl-N-dodecyl-N,N-bis(beta-hydroxyethyl)ammonium chl4ride; N-dodecyl-N-benzyl-N,N-dimethylammoniùm chloride; N-benzyl-N,N-dimethyl-N-(Cl2-Cl8-alkyl) ammonium chloride; N-dodecyl-N, N-dimethyl -N-ethylamm. onium ethylsulphate; N-dodecyl-N,N-dimethyl-N-(l-naphthylmethyl)ammonium chloride; N-hexadecyl-N,N-dimet~,yl-N-benzylammonium chloride; N-dodecyl-N , N- dimethyl -~-benzylammonium chloride and: l - (3 - nh l or4allyl ) - 3, 5, 7 -triaza-l-azonia-,~ chloride; urea A~r;v~t;vPc such as 1,3-bis(hyl~ yl)-5,5-dimethylhydantoini bi5(hydroxymethyl)ureai 3-(3,4-dichloroPhenyl)-l,l-dimethylurea; 3-(4-isoPropylphenyl)-l,l-dimethylurea; tetrakis (hydroxy-methyl) acetylene diurea; 1-(hylL~ yl)-5,5-dimethylhy~antoin and lm;fl~7nl;fl;nylurea; amino c4mPounos such as 1,3-bis(2-ethyl-hexyl)-5-methyl-5-amino-hexahydropyrimidine; hexamethyl~n~t, nt~; l,3-bis~4-amino-phen4xy)propane~; and 2-[(~lylLw~ lyl)-amino]eth~nol; imidazole derivatives such as 1 [2- (2, 4-dic-hloro-phenyl) -2- (2-propenyloxy) ethyl] -~ = . ... , _ _ _ _ _ _ _ _ _ _ WO 9S/337S~ 2 1 9 0 1 5 5 PCT/GB9SI01206 LI-imidazole; 2- (metl~y-clLL~lyl-amino) -hPn71m;tl;~7rl; 1-deeyl-3-dodecyl-2-methyl ;mi~1~7nl illm bromide; dodecylbis (l-decyl-2:methyl-;mirl~7nl ;1 ) -dibromide; nitrile ccmpounds such as 2-bromo-2-bromcmethyl-glutaronitrile, 2-ehloro-2-rhlnrn - -~hy7rlllt~rnn;~rilp~i 2,4~5,6-tetra-rhlnrn;Rnrhth~lnr~;nitrilP thioeyanate derivatives sueh as methylene(bis)thiocyanate; tin eompounds or complexes such as tributyltinoxide, chloride, nArhthn~tP7 benzoate or ~ ydLu~y~ udLe ;enth;;~7nl;n-3-oneg such as 4~5-trimethylene-4-;qnth;~7nlin-3-c~e~ 2-methyl-4,5-trimethylene-4-iqnthiA7nl;n-3-one, 2-methyliqnth;-7nlin-3-one, 5-ehloro-2-methyl-isothiazolin-3-one, hpn7;qnth; ~7nl;n-3-onei -2-methylhPn7iqnthi-7nlin-3-one, 2-octyliqnth;~7nlin-3-one~ 4,5-diehloro-2-oetylisothiazolin-3-one; N- (2-ethylbutyl)benzisothiazolin-3-cne); N- (n-hexyl)hPn7ienthi-7nlin-3-one; thiazole derivatives such as 2-(thiocyanomethylthio) -hPn7thi ;17nl P and merr~rtnhPn7thi ~7nl P; nitro eompr~unds sueh as tris(llydLu~ _ hyl)niLLI 'h~nP; ~-brc~mo-S-nitro-1,3-dioxane and 2-brOmO-2=nlLLU~LUU ul~-l,~=diOl; iodine ccmpounos sueh~ =as iodo propynyl butyl earbamate and tri-~iodo~allyl al~cohol, aldehydes and derivatives sueh as rlllt;~r~l lPhyde (rPnt~nPli~l), p-ehlorophenyl-3-iU~iU~LU~U L~yl hPmirnrm~l, formaldehyde and glyoxa1; amides sueh as rhlnr~ ~P; N~N-bis(hydLu~ llyl)rhlnr~ ~P; N-llydLu~ hyl-rhlnr~ P and dithio-272-his(benzmethyl amide); guanidine derivatives sueh as poly(hexamethylpnph;rJllAni~ip) and 1,6-hexamethylene-bis[5-(4-ehlorephenyl~biguanide]; ;mi~1~7nlil halides such as N,N'-dideeyl-2-methyl;m;~7nli bromide and 1,12-bis-(N-decyl-2-methylim;~l~7nli m)-dodecyl dibromidei thiones sueh as 3,5-dimethyltetrahydro-lr3,5-2~-th;nli-7inP-2-thione; triazine~derivatives sueh as hexahy~rntri~7;nP and 1,3,5-tri-(hydroxyethyI)-1,3,5-hexahydrotriazine, 6-ehloro-2,4-diethylamino-s-triazine and 4-ryelopropylamino-2-me~hyl~hio-6-t-hutylamino-s-triazine; nY 7nl;rlinP and derivatives thereof such as his-rY~7nli~inP; furan and derlvatives=
thereof sueh as 2,5-dihydm-2,5-dialkoxy-2,5-dialkylfurani earboxylie aeids and the salts and esters thereof such as sorbie aeid and 4-hydLu~ylJ~I~uie aeid and their salts and esters; phenol and derivatives thereof sueh as S-cloro-2-~2,4-dichloro-phenoxy)phenol; thio-bis(4-ehlorophenol) and 2-phenylphenol; sulphone derivatives sueh as hyl-paratolyl sulphone; 2, 3, 5, 6-tPtr rhl nro-4-(methylsulphonyl)pyridine and hPY~rhlnm~l;mPthyl sulphone; th;~ rlPq such as dimethyl~;th;~ ~ P and its metal eom~?lexes, ethylPnPhiq~;thi/ ` P and its metal o~mplexes, and 2-meeaptopyridine-N-oxide and its metal complexes and imides sueh as~
trichloromethylmerr-rtnrhth;~l ;m; lP, flllnm~irhlnrnmPthylmerr-rtnrhthi~limi~lP, and tr;rhl~ hylmerr~ntntPtr~hyrlrnrhth~lim; lP

~_ 2190155 }3 Further aspects of the present invention are described in the following illustrative examples in which all preparative ~Pt~ilC are given in parts by weight unless otherwise stated. The c~."~.ol~n~ were evaluated for their antimicrobial ~ eLLies under sterile conditions using the test protocols described below.
M; ~o~; t e .q~r~n p,~l n~nl for de1 D~; n; ~ ~T~
For h~ a An overnight culture (18 hours; 37C) of the d~ Liate micro-organism was prepared in nutrient broth to give d~okimately 109 viable cells per 1 ml of culture. 20 ~1 of the culture was then transferred aseptically to 20 ml of the nutrient broth. 200 ~l of this inoculum was then added to all vertical wells of a microtitre plate and 100 ~l inoculum added to each subsequent row of vertical wells.
A 5000 ppm solution of the chemical under test was prepared in an a~yL~yLiate solvent of which 20 ~l was added to the first well of the second row of vertical wells to act as control. The cnntPnts of each well were mLxed, 100 ~l withdrawn and transferred to adjacent hori~nt~1 wells in that row. This procesS was rPpe~te~ across each vertical row of wells to give a serial ~ ti~n of each c~rolm~ under test ranging from 500 ppm to 0.25 ~p",. The microtitre plate was then sealed and in~lhAtP~ at 25C for 42-48 hours. The min;mnm inhibitory c~n~Pntration (MIC) was indicated by the well with lowest ~ ration showing no visible bacterial growth.
For ~A~hAr2myce~ Cere* ~; A~
The culture was prepared as for bacteria except that Oxoid Malt broth was substituted for nutrient broth. Tn~lh~tion was for 42 to 72 hours at 30C.
For F~
The fungi were grown on a malt agar plate for one week at 25C and flooded with 2ml of sterile saline. Spores were released by careful agitation using a sterile loop. The spore suspension was poured into a Glass 25 ml Universal bottle. (Spore count approx 107ml~~).
20~1 of the spore suspension w~s then added to 20 ml of malt broth and used to inncnl~te the microtitre plate. Dil-lti~n~ were as described for the bacterial MIC and ;n~lh~ti~n was for 42-72 hours at pa;n1- F;lm P L,tr~nl This is identical to the Microtitre screen protocol except that the plates were ;n~lh~te~ for 4 days and the or~ni~m~ used were WO 95/337S~ 21 9 01 55 PCT/GB95/01206 fungi th~t had been isolated ~rom ~PtPr1nrA~Pil paint film sur~aces, namely rn~ri~ al ~Prn~ A) PRA FS 4 _ A~lr~nh~q;~ ~ p~ nq (AP) -- F~S FS 1 .---S rl~nq~nnril~m hPrh~r~lm (r~) r~n 162~3 . .=~
Ph~ vinl:Sr;z3 (PV) PR~ FS 13 st- yl i ~" d~ ) E~ FS 15 wo gs/33~sl 2 1 9 0 1 5 5 PCT/GB9~/01206 Exa=~1le 1 Preparation of 5- chlora- 1, 3-dihydro- 1 -hydraxy-2 ,1- ule ~Method B) .
a~ Pr~rstion rf 3-rhlrrohpn7;~ hyd~ trq~vl h~lr~;7i1~
A solutian of 3-rhlrrrh,-n7,31~,~hyde (15.56 par~.s; O.lO9M;
Aldrich~ in methylated spirits (40 ml~ was added slowly at below 10C to a stirred Rllqr~rqirn of p-toluene-sulphonylh~vdrazide (20 7 parts;
0.108M~ in methylated spirits (150 rnl~. The reaction mass was then sti~d at 20 to 25C for 1 hour and then heated at 60-70C for 13~ hours when the reactants and products dissolved~ The solvent was then removed by rotary evaporatian and the praduct was obtained as a solid which was slurried with ether ard washed with n-hexane. Yield = 27.2 parts (81.5%
theory~ mpt 122-3C.
Elemental analysIs Theory 54 . 5 6Ci 4 . 2%H; 9 .1%N
Found 54.5%C; 4.3%H; g.l%N
Proton NMR ( CDCl3: ppm) 8 . 5, s, 1~ ( -Nl~- ~; 7 . 9, d, 2P (Tosyl aromaticl; 7 . 7, s, 2 0 lE~ ( C~l=N~; 7 . 5 , s , lH (aromatic ~; 7 . 2 - 7 . 4 , m , 5H (Tosyl arrmatic~; 2 . 3, s , 3B ( -t~
b~ Prer~r~tion af titlo A ~qllqLr,~nqirn o~ anhydrous ferric chloride catalyst (0.75 parts, Fisons~ ln ary dichluLull,eLi,.,~e (20 ml~ was added at 20 to 25C
qimA71t~n~rAlq1y with boran tribromide (25 parts, O.lM, Aldrich) in dry lirhl ~ (100 mls) to a stirred qllqronqirn of the hydrazide from a) above (10.18 part, 0.033M~ in dry dichluLI h~n~ (160 mls) under a nitroo~n blar~cet The reactants were then stirred under reflux and the evolved hydrogen bromlde trapped under alueous sodium hydroxide. A~ter 3 haurs stirring at reflu3c, the reactants were allawed to stand at 20-25C for 48 hours and then stirred under reflux for a further 4 hours.
The reaction mass was then cooled and the salvent removed hy rotary evaporation. The solid obtained waR then stirred under reflux with 2N
~iodium hydr~xide solutian (160 ml) for 3 hours The hrown aoueous ~lqr~nqO n was e7ctracted with dichluL~ (50 ml), screened and then acidified to about pH 2 hy addition of 2N hydrachloric acid. The solid was filtered, slurried with rlirhl h~n~ (400 ml) and then washed with a saturated solution of sadium hi r~rhrn~t~ followed by water.
Yield = 24 parts ~43% theory~ . The solid was slurried in hot dichluL, ` ard filtered to give 0.36 =parts oxe3borole mp 140-45C.
The dichluL soluticl was cooled and the solid filtered giving a 5.J 2 ~ ~ ~ 1 5 5 PCT/GB9S/01~06 16 ~ =
further 0.35~ parts ox~horole ~p 146-8C The solids were combined and recrystallised from methylated spirits_ Yield = ~ ~1 parts ~9.2~ t~eory) mp 150-4C.
Elemental Analysis = ~ --S llLeory 49.8~6C, 3.5%H, 21 06~6Cl Fou~d 49.5%C, 3 596H, 21.0~Cl Proton NMR (cr,cl3) ppm 9.3, s, 1~(-C~t i 7.5, d, s, d, 3Htaromatic);
5 0, s, 2H ~ -O) . - -~e ~ Preparation of the PthAnnl: 'no ester nl~ ~nr~nnnhthAli~lP
(Method C) h~ lP ~0 2~ part, 0 00164M) was dissolved in toluene (40 ml) at 80C ar~d Pth~nnl ~-'nP ~.1 part,' 0.0016~q) added slowly. The ester formed; ''AtPly Toluene ~50 ml) was added, and the reactants heated to reflux to dissolve t~e ester. After scree~ling, the product separated on cooling as a pale solid 0 15 part (52% th~ory) mp 214-216C
Elemental Analysis ~ :
Theory 61~6C, 6.89iH, 7.9~sN
Found 60.3%C, 6.796H, 7.65iN
3 prPrArAtinn of 3 'nnnrn~n-l ester of~hirnnnrhthAli~P
This was prepared as descri'oed in example 2 hut using oornnnnhthAli~ip ~0 15 part, 0 00112M) and 3 nnrrn,nAnnl ~0.084 part, 0.00112M, Aldri~h) . The product was o'otained aq a rnlm~rlPqq solid by recryqtAlliqAtinn from toluene,/100-12~C petroleum ether.:
Yield = 0.18 part 184~ theory) mp = 174-6~C.
Elemental Analysis Iheory 62.8SiC; 7 3%H; 7.39~N
Found 64 . 596C; 7 . 5~6H; 7 .1~N
r 1~R 4-14 The MIC Q~ the followi~g i~ P deriv tives ~ràs ~lPtPrminP~l using the microtitre screen protocol described _ereinbefore In these exz~rples two fungi and two bacteria were used namely cPrPviqi;~P NCYC 124 (~3C~, A~Pr~ q n;~Pr CMI 17454 (AN), Ps ~PnlSrinnq~ NCIB 10421 (PA) and S'c:l~nnyln~nc~lq a3 NCIh 9518 (SA) .
The results are givsn in I~ble l below.
.

WO s5/337s~ 2 1 9 0 1 5 5 PCT/GBgc/~l2~6 TABI~: 1 Example Suostituent MIC date (ppm) org nism SC AN Pl~ SA
4 - 0 . 5 0 . 25 ~50 62 5 5 6 Cl- 2 2 N 62 6 5 PhO- 31 16 N 31 7 5 tert Bu- 125 62 N 31 8 5 F- ~0.25 <0.25 125 31 95, 6 fused Ph 31 16 N 16 10 10 4, 5 fused Ph 16 16 N 62 113 Ph- 16 31 N 125 125 Cl- 0.5 ~0.25 N 62 135 CF3- 8 0.25-0.5 125 62 145 Br- 8 1 N 125 ~ _ Frntnnt~. tn ~:lhl ~ 1 N = No activity at 100ppm level SC, AN, PA, SA are as described in the mirrrtitr~ screen r 1~ tn 1R
A 0.19~ ~w/w) solution of the flmr~ir;~s under test was prepared in 50/50 dioctylrhth~l~t~ and dioctyIadipate. Aliauots of 0.125, 0.25, 0.5, 2.0 and 3.0 mls~of each solution (to give 1.25, 2.5, 5, 20 and 30 ppm=~ungici~e) was adjusted in volume to 3 ~ 8 by adding the dioctylrhth~7At~7adipate mixture and then made up to 100ml with Potato De~ose Tryptone soya agar and ' _ ' q.-.l Plates were cast in petri dishes and allowed to set. Each plate was then inr,r71;~to~1, using a multi-point ~rrlir~tnr, with a 105 spore ellqrl~nqirn of AP, F5, PF and 5B and a 10' colony sllqn~nqinn of SW. The plates were incubated at 20C
for 4 days and the MIC value ~lF.tr.rminF~rl The results are aiven in Table 2 below.

~'O 9~/3375~ PCTIGB~5101206 Ecample ~.lhqti t~ nt F~ngi AP FS PP SB SW
15 - ~1.25 <1.25 <1 75 <1.25 <1.25 5 16 6 Cl- 20 20 2.5 2.5 2.5 17 5 Cl- ~1.25 ~1.25 <1.25 <1.25 5 18 5 F- <1.25 <1.25 <1.25 <1.25 <1.25 A SK 2.5 20 <1.25 2.5 2.5 B DS 60 80 4.0 2.5 2.5 F~tnnt~ to ~ l o 2 ~
SK = 2-n-octyl;qnthi~7nl;n-3-one DS = 2,3,5,6-t.~tr~rhlnrn-~4-methylsulphone)pyridine AP = ~llr~nh~3q;~1;l pullulans FS = ~8~m solani PP = Pen; ci l l i l lm plnophylum SB = Sc~ll~rl~q;q brevlcaulis SW = S~ Luv~l l;l-;ll;llm wa)csmanil 20 r l .~ 1q-2~ _ , , The MIC oi~ the following l, ","~ dpriva~t~Lues was, ~ t~=rm;n~tl using the palnt= ~ilm protc~rol descrihed h~r,~;nh~ r~, ~he values obtained are given ln Table 3~elow.
~ 3 Exam.~ple ~lhqt;t~ nt Or~anism PV CH AA AP SD

20 5 F- <0.25 0.5 <0.25 <0.25 ~0 .25 21 5 Cl- ~0.25 0.5 <0.25 <0.25 <0 .25 30 22 5 Br- 2 4 2 1 2 C SK 1 8 0.5 8 <0 . 25 D TP 0.8 0.8 0.4 0.4 0.8 F~t~ t-~ T~.hl ,. 3 SK = 2-n-octyl;qnth;~7nlin-3-one TP = i~ JL~ylly~oUtyl ~

Wo 95/337~1 PCTIGB9~/01206 Pr~rntive r l~w 2~ to 58 Example 1 a) and b) was repeated using the e~ui~alent weight Of hPn7~1~1Phyde and 3-fllmmhl~n7~1~1Phyde in place of the 3-chlornhPn7~1~Phyde used in Example la to obtai~ the An~l~cnlc 1,3-dihydro-l-hydraxy-2,1-h~-n7nY~hnrnlp flPrivatives. These bPn7nY~hnrnlP derivatives were then reacted with an alk~nnl;~-ninP as ~lf.c~-r;hPrl in Example 2 by replacirg the Pth~nnl~minP with the equivalent amDunt of ~ nnl~m;nP
The l~ r~.lP esters obtained have form~la 2 lQ R~CB\ R3R4 '~
~ ~
The elemental analysis and/or melting points of the ccrnpaunds cbtainPd are given in Table 4 below.

WO 9S133~54 2 1 9 0 ~ 5 5 PCT/GB95101206 Z Z Z Z Z Z Z Z Z Z Z Z Z Z
~ r ~n r N N
r r ~D r ~ o r ~ r.~ 0:1 ~ I N a~ N ID I r ~ c~
~ r r r r ~D r ~ o ~ r ~
U U U U U V U U U U U U V U
o ~ ~ o r ~ ~r o N N ~ ~D
~i N ~ N ~ N ~I r ~D o\ N .r Z Z!; Z Z Z Z Z Z Z Z Z Z Z z ~O .-1 0 N ~'I =l rl ~'1 .1 ~1 10 r r r r r Ln m m r r ~
r Ln,~ ~ o u~ r c~ N _I
~o r~ r r ~D r ~D ~ ID ~ ~c r r U U U U U U U U U U U U U U
~ u~~, .r u) ~ 111 o o ~ ~o ~ N 01 O ~ ~ N ri N ~ r m r N
Lr r o~ ~ r ~o r ~D N .r ~ 11'1 rl O
~ r ~ ~ ND rN r r ~ ~ D ~ r U ,, ~ N
U U U N ~_ N N N N , 5 N _ 5 U U U l_ , , , , , , , O) UU U U U U ~ . L 1~
~r c a~ o ~ N r~ D r c c~ o _I N
r~!l N N N N N N N r) r1 .. 1 r'l .-1 C 1'1 .'1 1~1 c ~ ~r ~

Z 2 Z z z z z z z z W
o r ~ I o o ~ ~D ~I rl ~ c~
= 5 ~ ~ _ ~ r ~ 5: 5D 5 5 ~ ~
~DO ~ N O\ 1~ 0 1'1 N ~ ) N
co~ r r r r ~ ~D c) r ~D ~D ID r U U U U U U U U U U U U U U
o o ~ c~ ~ ~ O O ~ .r N N N CO
r N N ~ ~ r r r ~ ~ ~ o Z Z Z Z Z Z Z Z Z Z Z Z Z Z
a~ r N .r ~ .-1 ~ O U7 Cl . 1`1 N N
m m r ~ ~ r ~
-& - 5 m ~ 5 5 ¢ - 5 ~D r) o m m ~ r ~ ~ ,~
r ~ r r r r ~ r ~ u/ ~ o r U U U U U U ~J t) U U U U U U
O ~ '1 ~ N CO ~0 .r ~r N O '7 ~
~D r N ~ ~ ~ U7 ~U ~C r o~ c~ ~ o c~
r o rl r r~ n ~ ~ 5 ~
I N N I r N N .I N N r N N _I
,~o ~ In r.l ~ r r~ ~ r ~ r o r ~D ,1 o N
,~E ~1 ,I N N ~1 _I N N _I N N ~1 _I N N _I

D ~ ~ D ~
~ ~ U ~ D ~ _ D
U U 5 5 X D~ D 3 U D~ X X IN ; ~ X
~ I I I I I I I I I I ~ I I I I I
P: 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 :) t~:.. & 5 5 5 5 5 5 5D 5 5 5 :C 5 5 U C~ ~ ~ ~ ~
~: 5 5 5 m Ll~ D D 5 5 5 2 5D m m ul ~n X ~ ~ ul ~ r ~ o ~I N 1.l .r ~ o r ~o .

WO 9!i/3375~ 2 1 ~ O 1 5 5 PCT/GB95/01206 22:
PL~ ~ 59--78 (~ Z1t 65 ..1~1 71) l~ese ~ c where pre~ared by an analogous method to that described in Example 1 a) and b) by replacing the 3=
chlornh,=n7~ hyde with an eau~valent amount of appropriate aldehyde.
I~e ~ derivatives. obtained have general ~ormula R8~o B
bH
Dle elemental analysis ana/or melting points o~. such o~mpounds are listed in ~able 5 below_ ~ _ WO 95/33754 2 1 9 0 1 5 5 PCT/GB95~01206 ~.
Z Z m m~ m~ Z m m m m ` N ' N = ~o .r r _I
N N r r ,I r _I = u) ~ ~ r o ~ m Ir :::
N N r r~ r~l ~ N In .r - U V V U V V U V V V U V
D N m ~ ~ N N r~l = .r 151 O
o~ r o~ m m o r ~ = u~
z Z m mh m~. Z m m o a ~ N
N O ~ ~D = r c m ~
~, m N 11~ rl r N _I In ~ O
U V U U V U U U V U
O ~ N
o~ r ~ ~ ~ r N ~D N ,~
o ~o r1 ~ r ,i r o ~r N N N
m ~ m 5~ r vZ ~
~ .
O V ~ lW ~ ~
u ~ u u~ ~o r . u u m ~ ~ v ~o v r~ r r r _I
X O~ O rl N ~ D r = o~ o ~ N r~ r c~
c r r r r r r r r r . .

WO 951337~ PCTIGB9S/01206 2~ ~01 55 PL.~ v, r l r 65 _ _ _ __ _ _ Pr~DAr~t;rn rf 3-~harul-l,3-~ ~ro-l-hylr~y-2.l-L~
a) PrenArAtinr of 1" ,~ p-trl--~nPq--lrhr,r~ylh~rA7rn,.
Fi,-,~, ,l,l,~,llllll- (15.0 parts, û.082M ex Fluka) was stirred at re_lux with p-toluene sulphonylhyorazine (15 33 parts, 0.[~82M ex Aldrich) in et-hanol (125ml) for~10 hours. Grad~ally a paIe yellow soluti~ formed from which the hydrazone gradually ~rPrinit;3tP~i A~ter o~oling to 20C, diethylether (20ml) was added and the hydrazone ~ :
filtered and washed with ether. The hydrazone was obtained as a wnite powder (24.0 parts; 8396 theory) mp 184-6CC
Proton ~IR Analysis 2.44 (s, 3H), 7.0-7.18 (m, 2H), 7.27-7.38 (m, 5H) 2.42-2.48 (m, 2H), 7.48-7.55 ~m, 4H), 7.56 (s, H) lS 7 . 86 (d, 2H) .
b) Pr~r;~r;~t1rn rf l~iA7Ahrr;nf~ rl~rivRti~e ~nhydrous ferric chloride :(0_75 parts) was suspended in dry ~lirhlrrrPth~nr (7s ml) and solutions of boron tr;hrrm;~ 131 ml æ M
solution in dichluLI ' ' , 0.131 M ex Aldrich~ and the hydrazorle :from (a) above ~(15_0 parts, 0.043M in dry dichloroeth~ne, 200 ml) added cilm~ltAnPr1cly at 20C os~er 15 mins with stirring under nitrogen. The t~ , ,..l Ille: rose by about 2~. 7he dark red reaction mix was stirred at reflux for 4% hr,urs to remove the hydrogen bromide.
The reactants were then cooled and drowned into ice (500 parts) and water (500 parts~ . The organic phase was separated and extracted with arueous sodium hydroxide solution. The aqueous layer was then separated and the pH adjusted to pH 3 by addition of,, a ,( ~ rl1 hyrlrrrhlnrir~ acid. This aoueous layer was extracted with rl~rhl~ hAnf~ which was then qFr~rRtr~l, dried r~er magnesium sulE~hate and the solvent removed to give the product as a cream solid. Yield =
3.83 parts ~249i theory) mp 239-42C.
Proton NMR Analysis ~ ~
2.44 (s, 3H), 7.33 (d, 2X), 7.37-7.52 ~m, 5H), 7.44 (s, H), 7.55-7.71 (m, 3X), 7.95 (d, 2H), 8.25-8.35 (m, H).
c) Pre~ArAtirn r~ ~itl~ c The riiA7qhrr;n~ from (b) (2.6 partsT was stirred at reflux in 109f aqueous potassium hydroxide solution (lOOml) rnnt~in;nj ethanol (SOml) for 4% hours. The solution was then cooled, washed with r7irhl~ hAnr and the pH adjusted to pH 3 with . "". "I 1 . l ,~
hy~lrnrhlnrir acid. A Cllqr,.~nqirn formed which was extracted into WO 95l3375~ PCTJGB9SJ0~20~i 21 9~1 55 r7irhll ~ h~nP After r~moval o_ the solvent, a pale cream solid was obtained which was fourd to be a mixture ol~starting material and product. This was purified by preparative column ch~-tr~rhy using a silica colu~n developea Wit7.1 r7irhl/ ~
~fter removiDg the solvent by ev~rrr~tirn, the p}t was obtained as a white solid ~0.49 parts; 249r theory) mp=145-7C
~roton NMR Analysis 6,14 (s, H), 7.15 (d, H), 7.21-7.46 (m, 7H), 7.83 (d, H), 8.51 (s, H) .
EL~ .,I ;V5 r 1P 71 Prar~r ~irn of 3-c~l-r--1. 3-rlil~rr-1-7~7roYy-2 .1-] .~ . ., . ,l r- a) Pre,n~r~tinn of 2-for~7~nhPr,ylhr~nir srir7 (Ref ~CS ~ 1964 p435) o-Tolyl boronic arid (10 partsi 0.0714 M ex Aldrich) and N-l 'rimif7P ~30,13g; 0.169 M ex Aldrich) were dried at 110C _or 16 hours. Both these reactants were added to carbon tPtr~rh7Orir7P
(450ml) ar~d 50ml of the solvent distilled off to remove any remaining water. Benzoyl peroxide (1.5 parts) was aaded and the reactarts stirred ur~der re_lux _or 6 hGurs. After cooling, cyclohexene (1.25 parts) was added to remove any bromine and the solution screened to remove qllrrin;m;r7P The product was then extracted with 15~f ar1ueous potassium hydroxide solution (4 x 35ml). ~These aoueous extracts were combined a~d acidified to about pH 4 with . ""( ~ Prl hy(1rrrhlrrir acid. The product was then extractea into diethylether (3 x 200rnl).
The combined ether extracts were then dried over magneSium sulphate and the et_er evaporated. Finally, the product was recrystallised from water. Yield 5 1 69 parts (15.39~ theory) mp 122-4C.
Elemental Analysis Found 55.3% C, 4.79~ H
Theory 56.09i C, 4.79r H
~ . -b) PrP,nRrRtirn of t;tlP cr~,rm~l (Ref JOC 2q 1964 p2172) 2-formyl phenyl ooronic acid (1.0 parts, 0.007 M) was added to an ao,ueous solution of soaium cyanide (0.35 parts) in water (20ml) at 20C with stirring. After 15 mins the reactarlts were cooled to 5C and carefully nPlltr~iRp~ to pH 5 with, ""~ l Prl hynrrrhlrrir acid. The itant white precipitate was filtered ar~a recrystallised from water WO gcl3~7~i PCT/GB /0 6 (25 ml) . m,he product was dried over calcium chIoride Yield = 0~29 parts (26% theory) mp = 114-5C _ =
Elemei.-ltal Analysi-S Found 59.0%, 3 5% ~, 8~6Y: N
mLheory 60~3%, 2~8% ~, 8~8% N~
F~ r l -Q 79 r-ri 80 Example 2 wa. repeated except that the ~th~nt~ was replaced by an e~uivalent amount of 8-hydr~yquinoline to give the le of Example 79~ Example B0 was obtained by replacin~ the hr7~.-.~hth~ of Exampie ~9 with the equivalent amoi~int of the 5-fliloro analogue~ The analytical data and/or melFlng point LS given ln m~able 6 below for the l~ le of for~ la~
XB_N/~
O~

æ z O
U~ Yl -~q U U
.~, tq ~o ~1 3 r ~D
~D
.e r O ~, O ~
~ _I
U
o t~
E ,1 ,1 -',4 o~ o r WO 9S/337~ 2 I q ~ 1 5 5 PCT/G139~/01206 Pren~t i ve r l ~q 81- 90 :
Preparati~re examples 23-58 -were: again repeated usin~
equivalent am~ounts of various aldehydeq and ~lk~nr~l~m;n~q to ~btain furt~r ~ esters of fc~nuia 2 ~
R7=~_NiR3R4 2 (5 Y
The m~elti~ points of these cor:ç~ounds are given in Table 7 below WO 95/337!i~ 2 1 q O 1 5 5 PCT~GB9~/01206 o N ,~ _I N N ~ N N N
1~ O N N O N
e ~ N N N N N
, ~
U U U ~ O ~ U U y ~, U ~ I

O U ~ 4~
U ~ U U U U U In 'D U
u~ Ir~ In In U~ ; In Ul ~J
E
~ = N 1~ D = = = CO

WO 9S/3375~ 2 1 9 3 1 5 5 PCT/GB95/01206 p~-r~t;re r la ~
Prarlr=tirn of s-math~ 3-dihy~lro-~-hy~rr~y-2~ ,.ul 2-~ , S mcthoxybenzylalcohoL (6~5 parts; 0.03M) wai dissolved in dry TEIF ~lOOmlT and cooli~i to :-78C n-Butyl-lithium (26.4 S ml of a 2.5 M solutior, in exanes ex al~drich, 0.066M) was added c*er 20 minutes with stirring under a nitrogen blanket ard keeping the tP~r=tllra below -60~C. After stirring for a further hour at -70C
HP:LC showed the reaction to be inrr~laf~ with 20~ startir~ material remaining. A further aliquot of r-butyl-lithium in hexanes (Sml;
0.0125M) was added and the reactants allowed~to warm to -50C. .
Tributylborate~(17.8mli 0.06f;M) was then ad(ied at between -70 and -5DC with stirring under a rltrogen blanket and the ~eactan~s allowed to warm to about 20C. Water (20ml) was ad~ed and the pH
adjusted to 10 with hydrochloric:~acid. After washing w1th diethylether, the pH of the aqueous phase was adjusted to pH 1-2 with hydrochlorlc acid anà washed with diethyl ether. The ether extract was washed with aoueous saturated brine, dried ov~r anhydrous magnesium sulphate and the ether e~=rrri~t~rl to leave the product as a pale oil (3.7 parts). =This was slurried with water rnnt~;ninrJ a little metha~ol whereupon a pirkish-white solid separated which wils filterad, washed with wa~er and dried (2.0 parts) mp = liO-115C after rec=ryqt~ c=tirn fi-om aqueous methanol .
p~ar= r:~ t i ve ~ 9 2 Prer~;~r=tirm rf 7-flllrro-l,3-dil~yr~ro-l-hy~lrrry-2 1-1.~
3-fll1rrrhan7yl alcohol (3.5 parts; 0.028 M) was stirred in TE~ (100 ml) rrnt=in;ng tetramethylene ethylPn~-l; n~ (10 2 mli 0 . 067M) . After cooling to -78C, sec-butyl=lit~ium (77ml of 0 8M
solution in cyclohexane ex Aldrich; 0.061M) was slowly added over 45 min at between -78 and -65C wi~h sti-rring under a nitrogen blanket. A~ter 1 hour at -78C, tributyl borate (16,78mli 0.06~M) was added drcpwise a~d the reactants stirred under nitrcgen for 16 hrs allowing the tF~mnar=t1lre to slowly raise to 20C~ ~Dilute hy~rrrh~rrir acid was added to bring the pH to ahout 12 and the arueous phase separated and washed with diethylether. The pH of the ar~ueous phase was then acidified to about pH 2 with hyrlrrrhlnrir acid and ~rtr=rtarl with~ ether ~3 x lOOml) .
T~ese ether extracts were washed with saturated brine, dried cver-magnesium sulphate and the ether evaporated whereupon the product separated as a pale solid (2.6 partsj=62~ theory~ mp = 132-134C after recryct=lli-=tirn from ar~ueous methanol.

WO 9513375~ PCT/GB9-,/01206 Prnr~ At~Ve r 1~ 93 Preparation of ~S
)==( o B
O
~lB,o a~ p~"nArAtinn rf 3-1 -2-fO~m1Y1th;n~hPnP
Ref Acta Cnem Scand 22 (1963) 4 1354 ~ =
2,3-dibrn~nthinrhPnP (14 parts, 0.058 M ex Lancaster Chemicals) was weighed into a reaction vessel er~uipped with a rl~bber septum. Dry diethyl ether (112 mls) was added by syringe through under a n'trogen blanket and cooled to -7DC. n-ButyI lithium (26.8 mls of 2.5 M solution ir hexa~es ex Aldrich) was slowly added over 20 mins.
After stirrir,g at -70C for 3~ hour, dimethylf~ ~P (6.3 parts) in diethyl ether was added over 5 mins. The reactants were allowed to warm to 20C, then lQ0 mls water was added with stirring. 'rhe ether solution was then washed with N hydrochloric acid, a~ueous h;rArhnnAtP and water.
Tne ethPr qnll.t;oll was then dried over magnesium sulphate and the ether e~AnnrAtP~l to leave a~ orange/brown oil (12.~2 parts). This oil was distilled at 0.~5 mm Pg and 68C to give a straw-coIoured oil (4.5 par'.s) . T_is oil was dissolved in ~l;rhl~ --hAnP and evaporated onto silica. This sili~a was formed into a colum-n an~ ~ie product separated by flash chrr-~-tr~r=rhy~ Tne silica column~was ~developed by washing with h~cane rrntAining increasing amounts of rl;rhl~ hAnP The prcduct was eluted in fractions rnn~in;n_ from 10-309c ~l;rhlnrr.n~thAnP
in hexene. ~
Yield = 4 . 05 parts .
Elemental Analysis: =
Found 32 . 096 C, 1. 3% ~, 16 . 7% S
Theory 31.4% C, 1.6% ~, 16.8% S
b) PrPr~r;~t;rn of 2- r3-1~rC~n-2-th; Pr~1~ -1, 3-d;r~1AnP
3_brOmO_2_fOrmY1th;rnhPnP (3.89 parts, 0.02 M) was heated at reflux with dry ethyleneglycol (1.6 parts~ toluene (25 par~s) and WO 9513375~ PCTIG~3!~5/01~06 21 ~1 55 p-toluene sulphonic acid ~0.1 parts) in a vessel equipped with a Dean and Stark separator for 16 b~urs. The reactants were tben co~le~ and ~rnr~t~ into silica. The silica was formed into a column w~nich was then developed by elution with hexane ~nnt;linin~ increasitg amaunts of dichl.,.~.. __~,.,,~. The product was obtained 'frnm frac~ions rnnt~inln~ 10-60~ ~;rhl~ h~n~ as a pale straw-coloured oil (4 42 parts) .
Elemental Analysis Found 35 . 6% C, 3 1% H, 13 6~ S
Theory 35.8% C, 3.0~ H, 13.796 S
c) Prer;~r~tinn of 2-fnrn~yl-3-thl~ ",ic ~
Butyl lithium (7.9 mI o~ 2.5 M solution in he,x",anes ex, Aldrich) was slowly,added,to a soluti,on r the dioxolane ~from ~b~, (4.28 rarts, 0.018 M) in dry diethylether with stirring at -70C under a nitrogen blanket After stirring for 15 mins but~yl borate (6 mls ex Aldrich) dissolved in ethylether (20ml~ was slowly ~added at -70C The reactants were stirred for a further 4 hours at -70C and then warmed to 20~C. 25 rnl N hydrochloric acid was,added and the reactants stirred i~or 1 hour at 20C T~ ~~th~r layer was then separated and sxtracted with N
aaueous sodium carbonate solution (3 x lOml) This,,aqueous carbonate solution was slowly acidified whereupon the product separa~ed and was filtered and dried. Yield - 0.89 parts.
25 Elemental l~nalysis ' ' Found 36.6% C, 3.0~ H, 19.6~ S
Theory 38.5~ C, 3.29~ H, 20.5% S
d) Prer~r~t;nn of tit~ n~
Ihe boronic acid _rom (c) 10.5 parts, 0.0032 M) was dissolved i~ ethanol and sodium borohydride ~3n mg ex Aldric~) ad~ed with stirring at 20C. :After 30 mins the reaction mass was evaporated onto silica which was formed into a column and dsveloped with h~cane ~nnt;~;nin~
in~rf.~c;n~ amounts of rlirhll h~nf. and th n rli~hl~ h~nF~
~nnt~in;n~ increasing amounts of methanol The product was obtained from fractio~s of ~l;rhl~ h~nF~ nnnt;.;n;n~ 3-4% methanol. After ev~rnr~tin~ the solvent, the product was recrystallised ~rom toluene.
Yield = 0.13 part mp ~03-4C.
Elemental Analysis Found 45.5% C, 3 29~ H, 23 . 3'6 S
Theory 45.8% C, 3.1~6 H, 26.4~6 S

~, 2190155 ~ The microbiological test data for this compound is AN CA AP GR PP EC PA SA BS

The legands are P~pl;7;nPc7l in the foGtnote to Table 8.
^nh; nl r~; 1~ Q 23 to 58 me MIC of the following h~n7C~horoie esters was determined against the micro-or~n;.qmq indicated in Table 8 for the cc~mrol7nc^7q of formula R ~ O
~ B' N+R3R~
O Y

R7 represents one or more substituents in the phenyl ring.
The test method em~Joyed was as follows.
The bacterial ;nc-7cl~l~ consisted of 24 hour cultures of the org~n; ~mq grown in Oxoid Nutrient broth, subcultured daily and incubated at 37C.
Spore suspPnq;c~nq of each of the test fungi were prepared in the following manner. To 250 ml conical flasks c~nt;7;n;ng well sporulating cultures of the fungi, growing on Oxoid Malt extract agar, a number of sterile 3mm glass beads and a~rC~xim;7tp]y 50 ml of a sterile solution of 0.01~ v/v of polyoxyalkylene (20) sorbitan mono-oleate (ex ICI as Tween 80 - Tween is a registered tradpm~rk) in water were added.
Each flask was swirled so that the beads Lc,.c~v~d the spores and the resulting sllqpPn.qic~n was poured into a sterile 100 gm medical flat bottle cc~nt;7;n;ng dyyLc~xim;7tply 50 ml of the sterile 0.01% v/v solution of Tween 80. The s7lqppn~i~n was storable for up to four weeks at 4C.
In the microbiological testing, the oxa~orazoles were tested at S, 25 and 100 ppm against the bacteria, yeast and fungi listed in the footnote to Table 8.

WO 95/3375~ 2 ~ ~ 31 5 5 PCT/GB9~/01206 N N N N N
111 N N N N N N r~ N N r~ r~ N N N N
CO N r~ r~ ~1 Z Z ~ Z N N r~
N r~ N N N N r; N N N N r~ N N N U~ O N N ri U N N r~ N N N N N N N 11~ N N N .--1 N N N
C ~ r U~ n ~r~ u~ ~- ~ u ~ ~1'~ 1/1 In U-~ In ~ In Ln C' 3 3 X 3 3 3 3 3 3 3 3 3 q S 3 3 3 3 3 3 3' 33 3 33 3 3 q 33 33 3 q 3 3 q q 3 3 3 U U U U U U h h h h h ~1: 3 3 3 111 Ul 11~ Il ) Ul Lll h 3 11~ 3 111 Ul m Ul 3' 3 3 _i r~ ~ Ul 10 1` r.) r~ o .1 N ~ ~ Itl 10 1` rA~ r~ O ~I N
h N N N N N N N r~ r~ r~ ~ .'1 ~ r~ r7 r~ r~
.

WO 9~51337~ 2 1 9 0 1 5 5 PCT/GB95/OIZ06 3 ~i -o o o o o U~ O N Z Z ~ N .~ ~I N N N N N N N
O O O O O
¢ul ul In 111 117 Itl Lll Itl O O O O O
O O O O O O
u In o o 111 ul o o o In 117 111 Lll o D . D U ~ D
U D J , D
~ 5 -- -- _ , e U U U U 5 ~ D ~r ~ 5U J u ~ u U
5 5 5 5 5 5' 5 5 5 5 5' 5; 5' m 5 5 5' 5 ., 5, 5' _ C~ ~ I 5 5 5 5 5 5 5 5 5 5 1 5' 5 U U ~ ~4 ~ ~
5 5 5 ~ 5 5 5, 5 5 5' 5~ 5 x ~ ~ o r l D a~ o ~ N rl ~ Ul l D r ~D

WO 951337~ 2 1 q ~ ~ 5 5 PCT/GB9~/01206 Fnntl~nt~ to T~ ~ 8 N = no activity at 100ppm level Control = 1~ 1P
AN =~Pr,~ lq niger S AP = ,~llrPnh~qi~il pullulans C~ ~ = SançLl~a albicans GR = ('.1; nol ~ ; ~seum 2P = pP~;o;l~ Tn pinophylum I~S = ~aCi~ subtilis EC = F~qchPriCh; A coli PA = Pse~nn~q aer~lgi.nQSa SA = St~lnrnrc Iq ~aureus Mi rroh; nl n.~ 1 F 1 Pq 59 tn 78 . - -Example~i 23 to s3 were repeated and the MIC value ~or ,l c~q o~ the ~ollowing ~structure ~PtPrm;nP l 2 0 R8~,o OH
Ri rPrrPqPntq o~e or more sllhctitllPntq in the phenyl ring.
The results ~re given~in Table 9 below_ ~

WO 9~13375~ 2 1 9 0 1 5 5 PCT/GB95/01206 .
m z N ~I N ~1 ~ Z Z N N ~ Z Z N ~A ~ N
u~ 2 N rl N ~1 ~I Z Z Z N _I t Z Z Z N .'1 Z
O Z Z ~ ~
O O O O L~l O
N rl _I N . 1 Z Z Z r~ _I N Z Z N N ~I ri O O O O
0 1~ O 111 0 111 z z Ir) ~O
o In D 111 Itl ~I N N U7 ~1 Ul N 111 N N Z Z 11 ~I N "
O O O
tll In z z Ltl N ~D

D r l Ul .-1 N N ~11 Z 111 N N .'1 N Z Z N ~1 ~I N
o o "~ o ) o o :': ~ ~ m ~ m ~ C/ ." ~
_I S U 4~ O ,~
O
,'1 C:
r ~ 0'1 0 ~I N ~ ~ Ul ~ r ~ O
O ~I N ~ ~D ~O U) r r r r r r r r r D

WO 9~/337~-1 PCT/CB9~/01206 21 9~1 55 ~

~ontnnte tn T; hl f. 9 Con';rol is i~ ,.,l1A~ 9 = ~9 =
S E 1 Gf~ 79 ~n~ A0 E~caTnples 23 to 5~ were r~eated and the MIC ~7alues l~or of th~ following stnlcture riF~trnnln~
Rl~
~ B/--N~ ~.
b ~
`~D' The results are given in Table 10 below.

WO 95/337~ 2 1 ~ O 1 5 5 PCT/GB95101206 ~9 N N
U~ N N
o In _I N
o _I N
P. It~
O~ N In C~ N 111 ~1 N 1~1 Ul In N 1~1 O
~3 1` C~

WO 95/337~J PCTlGn95/01206 PlACt;CA rlPtPr;r5~=n, 1P~ 34 36-s8. 68 An~l 80 _ .
DPtP~;nAti~n of A~t;vity A,~crA;nct plAqt;~-A rlPtPrio~enq E:xan~ples 15 to 18 were repeated using certain of the e~1les li8ted in E~ ples 23 to 7B. The activity of the various hPn7r~ h,~1 pq 5 is listed i~ Tahle 11 below Ihe exa~ale refOE~nce ~:bers listed ~n Tahle 8 and 9 are retained.
~ 3LE 1 1 10 Exam~ole AP FS PF SB SW
23 1.25 1.25 1.25 1.25 2.5 24 1.25 1.25 2.5 2.5 5.0 1.25 2.5 2.5 2.5 20 26 1.25 1.25 1.25_ 1.25 2.5 15 27 1.25 1.25 1.25 1.25 2.5 28 1.25 1.25 1.25 1.25 1.25 29 1.25 1.25 1.25 1.25 1.25.
1.25 1.25 1.25 1.25 1.25 31 1.25 1.25 1.25.~ 1.25 1.25 20 32 1.25 1.25 1.25 1.25 1.25 33 1.25 = 1.25 1.25 1.25 1.25 34 1.25 1.25 1.25 1.25 1.25 36 1.25 1.25 1.25 1.25 5.0 37 1.25 1.25 1.25 1.25 5.0 25 38 1.25 1.25 1.25 1.25 5.0 39 1.25 1.25. 1.25 1.25 5.0 4a 2.5 1.25 1.25 1.25 1.25 WO 95I3375~ PCTIGB95/01206 T~Rr.r.~ nn~ n~
Example AP FS PF SB SW
41 1.25 1.25 1.25 1.25 1.25 5 42 2.5 2.5 1.25 1.25 1.25 43 2.5 2.5 1.25 1.25 1.25 44 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 46 1.25 1.25 1 25 1.25 1.25 10 47 1.25 1.25 1.25 1.25 1.25 43 1.25 1.25 1.25 1.25 1.25 49 1.25 1.25 1 25 . 1.25 1.25 1.25 1.25 1.25 1 25 1.25 51 1.25 1.25 1.25 1.25 1.25 15 52 l . 2s l . 25 1 . 25 1 . 25 1 . 25 53 1.25 1.25 1.25 1.25 1.25 54 5.0 1.25 5.0 1.25 5.0 2.5 1.25 1.25 1.25 1.25 56 1 25 1.25 1.25 1.25 1.25 20 57 1.25 1.25 1.25 1.25 1.25 58 1.25 1.25 1.25 1.25 1.25 68 5.0 5.0 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 Control 1 2.5 2.5 2.5 2.5 20.0 25 Control 2 2.5 20 2.5 1.25 1.25 Fontnntf~ t~- T~l.l c. 11 Control 1 is 1~.,.,,,,,1,l,l~,,,1;~1~
Cc~trol 2 is 2-n-octyli~nt7~;A7nlin-3-c~Le

Claims (25)

1. A method for the protection of a medium susceptible to microbial attack by the treatment of the medium with an effective amount of an oxaborole of formula (1) or a salt thereof:
wherein A and D are each, independently, hydrogen, optionally substituted C1-18-alkyl, aralkyl, aryl or heterocyclyl or where A and D
together with the carbon atoms to which they are attached form a 5,6 or 7-membered fused ring which itself may be substituted;
X is a group -CR1R2 wherein R1 and R2 are each, independently, hydrogen, optionally substituted C16-alkyl, nitrile, amino, aryl or aralkyl or R1 and R2 together with the carban atom to which they are attached form an alicyclic ring;
R is hydrogen, optionally substituted C1-18-alkyl, aralkyl, aryl, cycloalkyl or a radical of formula (2) wherein A, D and X are as hereinbefore defined except where the medium is aviation fuel and the only oxaborole is boronophthalide.

2. A method as claimed in Claim 1 wherein A and D together with the carbon atoms to which they are attached form an optionally substituted fused phenyl ring.

3. A method as claimed in Claim 2 wherein the substituent is halogen.

4. A method as claimed in any one of claims 1 to 3 wherein R is hydrogen.

5. A method as claimed in any one of claims 1 to 3 where the oxaborole is a compound of formula 3 wherein A, D and X are defined in claim 1;
R3 and R4 are each, independently, hydrogen, optionally substituted C1-18-alkyl or optionally substituted phenyl or R3 together with Y or part of Y forms a 5-, 6- or 7-membered ring containing the nitrogen atom; and Y is an optionally substituted divalent alkylene linking group containing up to 18 carbon atoms.

6. A method as claimed in claim 5 wherein the oxaborole is a compound of formula 4 (4) wherein A, D and X are as defined in claim 1;
n is 1,2 or 3;
R3 is hydrogen, optionally substituted C1-18-alkyl or optionally substituted phenyl; and R5 and R6 are each, independently, hydrogen, optionally substituted alkyl containing up to a total of 16 carbon atoms or optionally substituted phenyl.

7. A method as claimed in either claim 5 or claim 6 wherein A
and D together with the carbon atoms to which they are attached form an optionally substituted fused phenyl ring.

8. A method as claimed in any one of claims 1 to 7 wherein the medium is a paint film or a plastics material.

9. A compound of formula (1) or a salt thereof wherein A, D, X and R are as defined in Claim 1 except for N-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yl)-succinamic acid; 6-nitro-, 6-amino-, 7-methyl-, 6-(NN-dimethylamino)-, 5-(NN-dimethylamino)-, 4-bromo-, 6-methyl-, 5-bromo-6-methylol-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; boronophthalide; 1-benzyloxy-, 1-cyclohexyloxy-, 1-ethoxy-1,3-dihydro-2,1-benzaxaborole; 1,1'-oxybis[1,3-7;hydro-2,1-benzoxaborole];1,1'-oxybis[4-bromo-1,3-dihydro-2,1-benzoxaborole] and 3,7-dihydro-1,5-dihydroxy-1H,3H-benzo[1,2-c: 4,5-c']bis[1,2]oxakorole.

10. A compound of formula 3 wherein A, D and X are defined in claim 1;
R3 and R4 are each, independently, hydrogen, optionally substituted C1-18-alkyl or optionally substituted phenyl or R3 together with Y or part of Y forms a 5-, 6- or 7-membered ring containing the nitrogen atom; and Y is an optionally substituted divalent alkylene linking group.

11. A ccmpcund as claimed in either claim 9 or claim 10 wherein A
and D together with the carbon atoms to which they are attached form an optionally substituted fused phenyl ring.

12. A compound as claimed in claim 11 wherein the fused phenyl ring contains halogen.

13. A compound as claimed in claim 10 which is 5- or 6- chloro, 5- or 6-bromo or 5- or 6-fluoro benzoxaborole.

14. A compound as claimed in any one of claims 10 to 12 which is an ester derived from 5- or 6-chloro, 5- or 6-bromo or 5- or 6-fluoro benzoxarole.

15. A composition comprising a carrier and an oxaborole of formula 1 or a salt thereof:
wherein A and D are each, independently, hydrogen, optionally substituted C1-18-alkyl, aralkyl, aryl or heterocyclyl or where A and D
together with the carbon atoms to which they are attached form a 5,6 or 7-membered fused-ring which itself may be substituted;
X is a group -CR1R2 wherein R1 and R2 are each, independently, hydrogen, optionally substituted C16-alkyl, nitrile, amino, aryl or aralkyl or R1 and R2 together with the carbon atom to which they are attached form an alicyclic ring;
R is hydrogen, optionally substituted C1-18-alkyl, aralkyl, aryl, cycloalkyl or a radical of formula (2) wherein A, D and X are as defined in claim 1.

16. A compositian as claimed in claim 15 wherein the carrier is a paint film or a plastics material.

17. A composition as claimed in claim 16 wherein the plastics material is placticised PVC or polyurethane.

18. A composition as claimed in claim 15 wherein the carrier is a stabilised or plasticiser for a plastics material.

19. A composition as claimed in claim 18 wherein the stabiliser or plasticiser is dioctylphthalate, dioctyl adipate or expoxidised soya bean oil.

20, A process for making an oxaborole of formula 1 wherein A and D together with the carbon atoms to which they are attached form a fused phenyl ring which comprises reating on o-substituted halogen toluene with magnesium or alkyl-lithium in a inert solvent and reacting the Grignard reagent or aryl lithium so formed with a borate ester to obtain a toluene boronic acid which is then reacted with a brominating agent followed by hydrolysis to give a hydroxymethylbenzene boronic acid and cyclising the boronic acid under acid conditions to give a benzoxaborole.

21. A process for making an oxaborole of formula 1 wherein A and D together with the carbon atoms to which they are attached form a fused phenyl ring which comprises reacting an optionally substituted benzaldehyde with p-toluenesulphonylhydrazide in an inert solvent followed by reaction with boron tribromide and catalyst to give a 1,2-dihydro-1-hydroxy-2-(4-methylphenylsulphonyl)-2,3,1-benzodiazaborine which is then hydrolysed and cyclised to form a benzoxaborole.

22. A process for making an oxaborole ester as claimed in claim 5 which ccmprises reacting an oxaborole of formula 1 where R is hydrogen with an amino-aliphatic carboxylic acid or alkanolamine in an inert solvent at 25-125°C.

23. A process for making an oxaborole of formula 1 wherein A and D together with the carbon atoms to which they are attached form a fused aromatic ring which comprises reacting an aromatic compound containing a -CH2OH group with alkyl or aryl-lithium and an organo-horate in a dry inert liquid.

24. A process as claimed in claim 23 wherein the aromatic compound containing a -CH2OH group also contains one or more further substituents which are ortho-lithiation activating groups.

25. A process for mixing an oxaborole of formula 1 wherein A and D together with the carbon atoms to which they are attached form a fused aromatic ring which ccmprises reacting an aromatic compound containing a -CH2OH group,and an ortho chloro or fluoro group with alkyl or aryl lithium and an organo-borate in an inert organic liquid.